In the last decade, CAR-T therapy has revolutionised the blood cancer landscape with several approvals, but manufacturing and administering it is complex. In the blood cancer field, immunotherapies such as bispecific antibodies and antibody-drug conjugates (ADCs) are often used alone or in combination in earlier treatment lines for acute diseases; CAR-Ts are commonly relegated as a last resort. Small-molecule tyrosine kinase inhibitors (TKI) are the gold standard for many chronic malignancies. At the American Society of Clinical Oncology (ASCO) Annual Meeting, 31 May to 4 June, several notable late-breaking studies were presented for haematological malignancies.
ASC4FIRST (NCT04971226)
In 2001, Gleevec (imatinib) became the first tyrosine kinase inhibitor (TKI) FDA-approved for cancer, indicated for adults with Philadelphia-positive chronic myeloid leukaemia (CML). Gleevec was a game-changer, as patients on the therapy could achieve a life expectancy on par with the healthy population. Since then, second generation TKI’s Tasigna (nilotinib), Sprycel (dasatinib), and Bosulif (bosutinib) with a similar mechanism of action have entered the market, along with imatinib, becoming the preferred regimens for the primary treatment of chronic phase (CP) CML. Novartis’ Scemblix (asciminib), a first-in-class TKI indicated for CP CML patients previously treated with two or more TKIs, contains a novel mechanism of action (MOA) that is highly specific. The investigators rationalised that Scemblix may be a safer long-term option for newly diagnosed CP CML patients, as currently approved TKIs are prone to adverse events such as pleural effusion affecting their adherence. At 48 weeks, Scemblix achieved a 67.7% major molecular response in the open-label trial’s primary endpoint compared to 49% in the investigator-selected TKI (IST) arm, which lumped imatinib and 2nd generation TKI patients. The discontinuation rate due to adverse events (AEs) for Scemblix was 5%, while it was 10% for IST. The study can prove to be practice-changing, but longer-term follow-up data is necessary to evaluate progression-free survival (PFS) and duration of response (DoR). For those who achieve deep remission, the effects of discontinuing the therapy must be assessed. Critiquing the ASC4FIRST trial objective is justified as a comparison of Scemblix with second-generation TKIs was not a primary endpoint. Scemblix only showed an 8.2% benefit in major molecular response (MMR) (66% vs. 57.8%), which is not considered significant. Payers may caution against coverage of a higher-priced drug that is prescribed indefinitely if its primary benefit is a reduction in an overall low drop-out rate. Nevertheless, the improved MMR and discontinuation rates due to AEs are promising for the Novartis drug, which is the basis for GlobalData projecting a sharp rise in sales for Scemblix surpassing $1 billion by 2026, up from $413 million last year.
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ECHELON-3 (NCT04404283)
Patients with R/R diffuse large B-cell lymphoma (DLBCL) who are ineligible or have progressed on CAR-T or HSCT have a poor prognosis. The ECHELON-3 investigators combined Pfizer’s CD30-directed antibody-drug conjugate (ADC) Adcetris (brentuximab vedotin) with lenalidomide and rituximab. The triplet therapy was compared to the combination of lenalidomide and rituximab in the control arm. Patients included in the study had already received at least two prior lines of therapy. At a median follow-up of 16 months, the trial met its primary endpoint of overall survival as patients on the triplet regimen lived for 13.8 months vs. 8.5 months in the control (hazard ratio [HR], 0.62). The experimental arm beat the control in secondary measures such as mPFS (4.2 months vs. 2.6 months), ORR (64.3% vs. 41.5%), and complete response (CR) (40.2% vs. 18.6%). Subgroup analysis shows patients who expressed low amounts of CD30 maintained a strong ORR/CR (60.5%/40.8%). Grade ≥ 3 adverse events were higher in the experimental arm (88% vs. 77%). Although the results were promising for Pfizer, the ADC would need to contend with competing therapies of the same drug class, such as Roche’s Polivy (polatuzumab vedotin) in combination with bendamustine and rituximab, as well as ADC Therapeutic’s Zynlonta (locastuximab tesirine). Polivy also has a frontline label in combination with R-CHOP. Adcetris and Polivy share the same MMAE drug payload, and the field currently lacks data suggesting an MMAE-based ADC followed by a second MMAE-based ADC in a later line is effective. GlobalData anticipates Adcetris, which has seven labels, will see its sales peak to $2.1 billion by 2030.
DREAMM8 (NCT04484623)
GSK’s BCMA-targeted ADC Blenrep (belantamab mafodotin), once approved for heavily pretreated multiple myeloma (MM), saw its label revoked after failing its confirmatory study. The company plans a market return based on encouraging findings from the Phase III DREAMM-7 (NCT04246047) and DREAMM-8 studies for R/R MM. The latter study, which combined Blenrep with BMS’ Pomalyst (pomalidomide) and dexamethasone, was presented at the conference. At a median follow-up of 21.8 months, mPFS, the study’s primary endpoint, was not reached, while the comparator arm that combined bortezomib with pomalidomide and dexamethasone had a 12.7-month PFS (HR:.52). At 12 months, the mPFS on the Blenrep arm was 71% vs. 51% in the control. The ORR in the Blenrep group was slightly higher than in the control (77% vs. 72%), but the depth of response was significantly higher in the experimental arm, as 40% of patients had a CR, compared to only 16% in the control. Survival data is currently immature but is trending positive (HR:.77). Severe eye toxicity is associated with Blenrep, and 83% of patients experienced a dose interruption. Dose modifications were developed to mitigate this side effect, and only 9% of patients stopped treatment due to eye toxicity. Non-ocular AEs were similar in both arms. While GSK intends to relaunch, it faces fierce competition in the space. There’s no shortage of options for R/R MM with the likes of Johnson & Johnson’s CAR T therapy Carvytki (clitacabtagene autoleucel) and BMS’ Abecma (idecabtagene vicleucel), as well as the bispecific antibody Tecvayli. Physicians may prefer these other options, especially in earlier treatment lines, to prescribing the ADC with a checkered past, which requires careful monitoring and dose modifications.
